Bio
Research interests: Genetic mechanism underlying mitochondrial pathology, neurodegeneration, and muscle loss using Drosophila as a model organism.
Honors & Awards
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Young Investigator Award, Korean Drosophila Research Society (2019)
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Invited speaker at the 73rd annual conference, The Korean Association of Biological Sciences (2018)
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Global scholarship award for foreign graduate students, Kookmin University (2016)
Professional Education
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Bachelor of Science, Tribhuban University (2010)
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Doctor of Philosophy, Kookmin University (2019)
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Master of Science, Tribhuban University (2014)
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PhD, Kookmin University, Molecular Genetics (2019)
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MS, Tribhuvan University, Medical Microbiology (2013)
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BS, Tribhuvan University, Microbiology (2010)
All Publications
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The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1.
Proceedings of the National Academy of Sciences of the United States of America
2024; 121 (39): e2400531121
Abstract
It is well established that DNA Damage Regulated Autophagy Modulator 1 (DRAM1), a lysosomal protein and a target of p53, participates in autophagy. The cellular functions of DRAM1 beyond autophagy remain elusive. Here, we show p53-dependent upregulation of DRAM1 in mitochondrial damage-induced Parkinson's disease (PD) models and exacerbation of disease phenotypes by DRAM1. We find that the lysosomal location of DRAM1 relies on its intact structure including the cytosol-facing C-terminal domain. Excess DRAM1 disrupts endoplasmic reticulum (ER) structure, triggers ER stress, and induces protective ER-phagy. Mechanistically, DRAM1 interacts with stromal interacting molecule 1 (STIM1) to tether lysosomes to the ER and perturb STIM1 function in maintaining intracellular calcium homeostasis. STIM1 overexpression promotes cellular health by restoring calcium homeostasis, ER stress response, ER-phagy, and AMP-activated protein kinase (AMPK)-Unc-51 like autophagy activating kinase 1 (ULK1) signaling in cells with excess DRAM1. Thus, by promoting organelle contact between lysosomes and the ER, DRAM1 modulates ER structure and function and cell survival under stress. Our results suggest that DRAM1 as a lysosomal protein performs diverse roles in cellular homeostasis and stress response. These findings may have significant implications for our understanding of the role of the p53/DRAM1 axis in human diseases, from cancer to neurodegenerative diseases.
View details for DOI 10.1073/pnas.2400531121
View details for PubMedID 39292746
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Translation stalling induced mitochondrial entrapment of ribosomal quality control related proteins offers cancer cell vulnerability.
Research square
2024
Abstract
Ribosome-associated quality control (RQC) monitors ribosomes for aberrant translation. While the role of RQC in neurodegenerative disease is beginning to be appreciated, its involvement in cancer is understudied. Here, we show a positive correlation between RQC proteins ABCE1 and ZNF598 and high-grade muscle-invasive bladder cancer. Translational stalling by the inhibitor emetine (EME) leads to increased mitochondrial localization of RQC factors including ABCE1, ZNF598, and NEMF, which are continuously imported into mitochondria facilitated by increased mitochondrial membrane potential caused by EME. This reduces the availability of these factors in the cytosol, compromising the effectiveness of RQC in handling stalled ribosomes in the cytosol and those associated with the mitochondrial outer membrane (MOM). Imported RQC factors form aggregates inside the mitochondria in a process we term stalling-induced mitochondrial stress (SIMS). ABCE1 plays a crucial role in maintaining mitochondrial health during SIMS. Notably, cancer stem cells (CSCs) exhibit increased expression of ABCE1 and consequently are more resistant to EME-induced mitochondrial dysfunction. This points to a potential mechanism of drug resistance by CSCs. Our study highlights the significance of mitochondrial entrapment of RQC factors such as ABCE1 in determining the fate of cancer cells versus CSCs. Targeting ABCE1 or other RQC factors in translational inhibition cancer therapy may help overcome drug resistance.
View details for DOI 10.21203/rs.3.rs-4899860/v1
View details for PubMedID 39315278
View details for PubMedCentralID PMC11419255
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Ribosome stalling during c-myc translation presents actionable cancer cell vulnerability.
PNAS nexus
2024; 3 (8): pgae321
Abstract
Myc is a major driver of tumor initiation, progression, and maintenance. Up-regulation of Myc protein level rather than acquisition of neomorphic properties appears to underlie most Myc-driven cancers. Cellular mechanisms governing Myc expression remain incompletely defined. In this study, we show that ribosome-associated quality control (RQC) plays a critical role in maintaining Myc protein level. Ribosomes stall during the synthesis of the N-terminal portion of cMyc, generating aberrant cMyc species and necessitating deployment of the early RQC factor ZNF598 to handle translational stress and restore cMyc translation. ZNF598 expression is up-regulated in human glioblastoma (GBM), and its expression positively correlates with that of cMyc. ZNF598 knockdown inhibits human GBM neurosphere formation in cell culture and Myc-dependent tumor growth in vivo in Drosophila. Intriguingly, the SARS-COV-2-encoded translational regulator Nsp1 impinges on ZNF598 to restrain cMyc translation and consequently cMyc-dependent cancer growth. Remarkably, Nsp1 exhibits synthetic toxicity with the translation and RQC-related factor ATP-binding cassette subfamily E member 1, which, despite its normally positive correlation with cMyc in cancer cells, is co-opted by Nsp1 to down-regulate cMyc and inhibit tumor growth. Ribosome stalling during c-myc translation thus offers actionable cancer cell vulnerability.
View details for DOI 10.1093/pnasnexus/pgae321
View details for PubMedID 39161732
View details for PubMedCentralID PMC11330866
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Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.
Nature communications
2024; 15 (1): 1637
Abstract
Translational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. Here we show that ZNF598 undergoes regulatory K63-linked ubiquitination in a CNOT4-dependent manner and is upregulated upon mitochondrial stresses in mammalian cells and Drosophila. ZNF598 promotes resolution of stalled ribosomes and protects against mitochondrial stress in a ubiquitination-dependent fashion. In Drosophila models of neurodegenerative diseases and patient cells, ZNF598 overexpression aborts stalled translation of mitochondrial outer membrane-associated mRNAs, removes faulty translation products causal of disease, and improves mitochondrial and tissue health. These results shed lights on the regulation of ZNF598 and its functional role in mitochondrial and tissue homeostasis.
View details for DOI 10.1038/s41467-024-45525-3
View details for PubMedID 38388640
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RACK1 and IRE1 participate in the translational quality control of amyloid precursor protein in Drosophila models of Alzheimer's disease.
The Journal of biological chemistry
2024: 105719
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by dysregulation of the expression and processing of the amyloid precursor protein (APP). Protein quality control systems are dedicated to remove faulty and deleterious proteins to maintain cellular protein homeostasis (proteostasis). Identidying mechanisms underlying APP protein regulation is crucial for understanding AD pathogenesis. However, the factors and associated molecular mechanisms regulating APP protein quality control remain poorly defined. In this study, we show that mutant APP with its mitochondrial-targeting sequence ablated exhibited predominant endoplasmic reticulum (ER) distribution and led to aberrant ER morphology, deficits in locomotor activity, and shortened lifespan. We searched for regulators that could counteract the toxicity caused by the ectopic expression of this mutant APP. Genetic removal of the ribosome-associated quality control (RQC) factor RACK1 resulted in reduced levels of ectopically expressed mutant APP. By contrast, gain of RACK1 function increased mutant APP level. Additionally, overexpression of the ER stress regulator (IRE1) resulted in reduced levels of ectopically expressed mutant APP. Mechanistically, the RQC related ATPase VCP/p97 and the E3 ubiquitin ligase Hrd1 were required for the reduction of mutant APP level by IRE1. These factors also regulated the expression and toxicity of ectopically expressed wild type APP, supporting their relevance to APP biology. Our results reveal functions of RACK1 and IRE1 in regulating the quality control of APP homeostasis and mitigating its pathogenic effects, with implications for the understanding and treatment of AD.
View details for DOI 10.1016/j.jbc.2024.105719
View details for PubMedID 38311171
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Reverse electron transfer is activated during aging and contributes to aging and age-related disease.
EMBO reports
2023: e55548
Abstract
Mechanisms underlying the depletion of NAD+ and accumulation of reactive oxygen species (ROS) in aging and age-related disorders remain poorly defined. We show that reverse electron transfer (RET) at mitochondrial complex I, which causes increased ROS production and NAD+ to NADH conversion and thus lowered NAD+ /NADH ratio, is active during aging. Genetic or pharmacological inhibition of RET decreases ROS production and increases NAD+ /NADH ratio, extending the lifespan of normal flies. The lifespan-extending effect of RET inhibition is dependent on NAD+ -dependent Sirtuin, highlighting the importance of NAD+ /NADH rebalance, and on longevity-associated Foxo and autophagy pathways. RET and RET-induced ROS and NAD+ /NADH ratio changes are prominent in human induced pluripotent stem cell (iPSC) model and fly models of Alzheimer's disease (AD). Genetic or pharmacological inhibition of RET prevents the accumulation of faulty translation products resulting from inadequate ribosome-mediated quality control, rescues relevant disease phenotypes, and extends the lifespan of Drosophila and mouse AD models. Deregulated RET is therefore a conserved feature of aging, and inhibition of RET may open new therapeutic opportunities in the context of aging and age-related diseases including AD.
View details for DOI 10.15252/embr.202255548
View details for PubMedID 36794623
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The mTORC2/AKT/VCP axis is associated with quality control of the stalled translation of poly(GR) dipeptide repeats in C9-ALS/FTD.
The Journal of biological chemistry
2023: 102995
Abstract
Expansion of G4C2 hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis with frontotemporal dementia (C9-ALS/FTD). Dipeptide repeats (DPRs) generated by unconventional translation, especially the R-containing poly(GR), have been implicated in C9-ALS/FTD pathogenesis. Mutations in other genes, including TAR DNA-binding protein 43 KD (TDP-43), fused in sarcoma (FUS), and valosin-containing protein (VCP), have also been linked to ALS/FTD, and upregulation of amyloid precursor protein (APP) is observed at the early stage of ALS and FTD. Fundamental questions remain as to the relationships between these ALS/FTD genes and whether they converge on similar cellular pathways. Here, using biochemical, cell biological, and genetic analyses in Drosophila disease models, patient-derived fibroblasts, and mammalian cell culture, we show that mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling is activated by APP, TDP-43, and FUS, and that mTORC2/AKT and its downstream target VCP mediate the effect of APP, TDP-43, and FUS on the quality control of C9-ALS/FTD-associated poly(GR) translation. We also find that poly(GR) expression results in reduction of global translation, and that the co-expression of APP, TDP-43, and FUS results in further reduction of global translation, presumably through the GCN2/eIF2alpha integrated stress response pathway. Together, our results implicate mTORC2/AKT signaling and GCN2/eIF2alpha integrated stress response as common signaling pathways underlying ALS/FTD pathogenesis.
View details for DOI 10.1016/j.jbc.2023.102995
View details for PubMedID 36764521
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Prevention of ribosome collision-induced neuromuscular degeneration by SARS CoV-2-encoded Nsp1.
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (42): e2202322119
Abstract
An overarching goal of aging and age-related neurodegenerative disease research is to discover effective therapeutic strategies applicable to a broad spectrum of neurodegenerative diseases. Little is known about the extent to which targetable pathogenic mechanisms are shared among these seemingly diverse diseases. Translational control is critical for maintaining proteostasis during aging. Gaining control of the translation machinery is also crucial in the battle between viruses and their hosts. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic. Here, we show that overexpression of SARS-CoV-2-encoded nonstructural protein 1 (Nsp1) robustly rescued neuromuscular degeneration and behavioral phenotypes in Drosophila models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These diseases share a common mechanism: the accumulation of aberrant protein species due to the stalling and collision of translating ribosomes, leading to proteostasis failure. Our genetic and biochemical analyses revealed that Nsp1 acted in a multipronged manner to resolve collided ribosomes, abort stalled translation, and remove faulty translation products causative of disease in these models, at least in part through the ribosome recycling factor ABCE1, ribosome-associated quality-control factors, autophagy, and AKT signaling. Nsp1 exhibited exquisite specificity in its action, as it did not modify other neurodegenerative conditions not known to be associated with ribosome stalling. These findings uncover a previously unrecognized mechanism of Nsp1 in manipulating host translation, which can be leveraged for combating age-related neurodegenerative diseases that are affecting millions of people worldwide and currently without effective treatment.
View details for DOI 10.1073/pnas.2202322119
View details for PubMedID 36170200
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Regulation of reverse electron transfer at mitochondrial complex I by unconventional Notch action in cancer stem cells.
Developmental cell
1800; 57 (2): 260
Abstract
Metabolic flexibility is a hallmark of many cancers where mitochondrial respiration is critically involved, but the molecular underpinning of mitochondrial control of cancer metabolic reprogramming is poorly understood. Here, we show that reverse electron transfer (RET) through respiratory chain complex I (RC-I) is particularly active in brain cancer stem cells (CSCs). Although RET generates ROS, NAD+/NADH ratio turns out to be key in mediating RET effect on CSC proliferation, in part through the NAD+-dependent Sirtuin. Mechanistically, Notch acts in an unconventional manner to regulate RET by interacting with specific RC-I proteins containing electron-transporting Fe-S clusters and NAD(H)-binding sites. Genetic and pharmacological interference of Notch-mediated RET inhibited CSC growth in Drosophila brain tumor and mouse glioblastoma multiforme (GBM) models. Our results identify Notch as a regulator of RET and RET-induced NAD+/NADH balance, a critical mechanism of metabolic reprogramming and a metabolic vulnerability of cancer that may be exploited for therapeutic purposes.
View details for DOI 10.1016/j.devcel.2021.12.020
View details for PubMedID 35077680
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Inefficient quality control of ribosome stalling during APP synthesis generates CAT-tailed species that precipitate hallmarks of Alzheimer's disease.
Acta neuropathologica communications
2021; 9 (1): 169
Abstract
Amyloid precursor protein (APP) metabolism is central to Alzheimer's disease (AD) pathogenesis, but the key etiological driver remains elusive. Recent failures of clinical trials targeting amyloid-beta (Abeta) peptides, the proteolytic fragments of amyloid precursor protein (APP) that are the main component of amyloid plaques, suggest that the proteostasis-disrupting, key pathogenic species remain to be identified. Previous studies suggest that APP C-terminal fragment (APP.C99) can cause disease in an Abeta-independent manner. The mechanism of APP.C99 pathogenesis is incompletely understood. We used Drosophila models expressing APP.C99 with the native ER-targeting signal of human APP, expressingfull-length human APP only, or co-expressing full-length human APP and beta-secretase (BACE), to investigate mechanisms of APP.C99 pathogenesis. Key findings are validated in mammalian cell culture models, mouse 5xFAD model, and postmortem AD patient brain materials. We find that ribosomes stall at the ER membrane during co-translational translocation of APP.C99, activating ribosome-associated quality control (RQC) to resolve ribosome collision andstalled translation. StalledAPP.C99 species with C-terminal extensions (CAT-tails) resulting from inadequate RQC are prone to aggregation, causing endolysosomal and autophagy defects and seeding the aggregation of amyloid beta peptides, the main component of amyloid plaques. Genetically removing stalled and CAT-tailed APP.C99 rescued proteostasis failure, endolysosomal/autophagy dysfunction, neuromuscular degeneration, and cognitive deficits in AD models. Our findingofRQC factor deposition at the core of amyloid plaques from AD brains further supports the central role of defective RQC of ribosome collision andstalled translation in AD pathogenesis. These findings demonstrate that amyloid plaque formation is the consequence and manifestation of a deeper level proteostasis failure caused by inadequate RQC of translationalstallingand the resultantaberrantly modified APP.C99 species, previously unrecognized etiological drivers of ADandnewly discovered therapeutic targets.
View details for DOI 10.1186/s40478-021-01268-6
View details for PubMedID 34663454
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Cucurbitacin B Activates Bitter-Sensing Gustatory Receptor Neurons via Gustatory Receptor 33a in Drosophila melanogaster.
Molecules and cells
2020; 43 (6): 530-538
Abstract
The Gustatory system enables animals to detect toxic bitter chemicals, which is critical for insects to survive food induced toxicity. Cucurbitacin is widely present in plants such as cucumber and gourds that acts as an anti-herbivore chemical and an insecticide. Cucurbitacin has a harmful effect on insect larvae as well. Although various beneficial effects of cucurbitacin such as alleviating hyperglycemia have also been documented, it is not clear what kinds of molecular sensors are required to detect cucurbitacin in nature. Cucurbitacin B, a major bitter component of bitter melon, was applied to induce action potentials from sensilla of a mouth part of the fly, labellum. Here we identify that only Gr33a is required for activating bitter-sensing gustatory receptor neurons by cucurbitacin B among available 26 Grs, 23 Irs, 11 Trp mutants, and 26 Gr-RNAi lines. We further investigated the difference between control and Gr33a mutant by analyzing binary food choice assay. We also measured toxic effect of Cucurbitacin B over 0.01 mM range. Our findings uncover the molecular sensor of cucurbitacin B in Drosophila melanogaster. We propose that the discarded shell of Cucurbitaceae can be developed to make a new insecticide.
View details for DOI 10.14348/molcells.2020.0019
View details for PubMedID 32451368
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Molecular sensor of nicotine in taste of Drosophila melanogaster
INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY
2019; 111: 103178
Abstract
Nicotine is an alkaloid and potent parasympathomimetic stimulant found in the leaves of many plants including Nicotiana tabacum, which functions as an anti-herbivore chemical and an insecticide. Chemoreceptors embedded in the gustatory receptor neurons (GRNs) enable animals to judge the quality of bitter compounds and respond to them. Various taste receptors such as gustatory receptors (GRs), ionotropic receptors (IRs), transient receptor potential channels (TRPs), and pickpocket channels (PPKs) have been shown to have important roles in taste sensation. However, the mechanism underlying nicotine taste sensation has not been resolved in the insect model. Here we identify molecular receptors to detect the taste of nicotine and provide electrophysiological and behavioral evidence that gustatory receptors are required for avoiding nicotine-laced foods. Our results demonstrate that gustatory receptors are reasonable targets to develop new pesticides that maximize the insecticidal effects of nicotine.
View details for DOI 10.1016/j.ibmb.2019.103178
View details for Web of Science ID 000478706500007
View details for PubMedID 31226410
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Mechanism of Acetic Acid Gustatory Repulsion in Drosophila
CELL REPORTS
2019; 26 (6): 1432-+
Abstract
The decision to consume or reject a food based on the degree of acidity is critical for animal survival. However, the gustatory receptors that detect sour compounds and influence feeding behavior have been elusive. Here, using the fly, Drosophila melanogaster, we reveal that a member of the ionotropic receptor family, IR7a, is essential for rejecting foods laced with high levels of acetic acid. IR7a is dispensable for repulsion of other acidic compounds, indicating that the gustatory sensation of acids occurs through a repertoire rather than a single receptor. The fly's main taste organ, the labellum, is decorated with bristles that house dendrites of gustatory receptor neurons (GRNs). IR7a is expressed in a subset of bitter GRNs rather than GRNs dedicated to sour taste. Our findings indicate that flies taste acids through a repertoire of receptors, enabling them to discriminate foods on the basis of acid composition rather than just pH.
View details for DOI 10.1016/j.celrep.2019.01.042
View details for Web of Science ID 000457709200007
View details for PubMedID 30726729
View details for PubMedCentralID PMC6490183
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Gustatory receptor 28b is necessary for avoiding saponin in Drosophila melanogaster
EMBO REPORTS
2019; 20 (2)
Abstract
Saponins function as a natural self-defense mechanism for plants to deter various insects due to their unpleasant taste and their toxicity. Here, we provide evidence that saponin from Quillaja saponaria functions as an antifeedant as well as an insecticide to ward off insects in both the larval and the adult stages. Using a behavioral screen of 26 mutant fly lines, we show that the Gr28b gene cluster plays a role in saponin avoidance in the labellum. The Gr28b mutant does not avoid saponin and exhibits increased lethality when fed saponin-mixed food. Tissue-specific rescue experiments with five different Gr28b isoforms revealed that only the Gr28b.c isoform is required for saponin sensation. We propose that in contrast to sensing many other bitter compounds, saponin sensing does not require the function of core taste receptors, such as GR32a, GR33a, and GR66a. Our results reveal a novel role for GR28b in taste. In addition, the ability of saponin to act as insecticides as well as antifeedants suggests its potential application in controlling insect pests.
View details for DOI 10.15252/embr.201847328
View details for Web of Science ID 000459026000012
View details for PubMedID 30622216
View details for PubMedCentralID PMC6362386
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The multidimensional ionotropic receptors of Drosophila melanogaster
INSECT MOLECULAR BIOLOGY
2018; 27 (1): 1–7
Abstract
Ionotropic receptors (IRs), which form ion channels, can be categorized into conserved 'antennal IRs', which define the first olfactory receptor family of insects, and species-specific 'divergent IRs', which are expressed in gustatory receptor neurones. These receptors are located primarily in cell bodies and dendrites, and are highly enriched in the tips of the dendritic terminals that convey sensory information to higher brain centres. Antennal IRs play important roles in odour and thermosensation, whereas divergent IRs are involved in other important biological processes such as taste sensation. Some IRs are known to play specific biological roles in the perception of various molecules; however, many of their functions have not yet been defined. Although progress has been made in this field, many functions and mechanisms of these receptors remain unknown. In this review, we provide a comprehensive summary of the current state of knowledge in this field.
View details for DOI 10.1111/imb.12347
View details for Web of Science ID 000419247300001
View details for PubMedID 28857341